Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common and often fatal complication after trauma. It affects from 11.8 to 68% of all trauma admissions and is a one of three leading causes of death among trauma patients surviving the first 24 hours. Currently, the central component of VTE prevention is pharmacologic therapy with heparin or its low-molecular- weight derivatives. Despite this prophylaxis, however, VTE rates remain high and the mechanism driving this phenomenon is not well understood. Recent studies have shown a possible link between VTE formation and the excessive activation of the innate immune system. These studies demonstrate that platelets, which are classically thought of as the principal components of the hemostatic system, play an important role in mediating inflammatory and thrombotic responses following trauma. However, the mechanism by which trauma leads to platelet activation and VTE formation is incompletely understood. To fill this knowledge gap, this proposal will test the hypothesis that platelet-specific NLRP3 inflammasome activation and resulting IL-1 release promote platelet aggregation and VTE formation following trauma. NLRP3 inflammasome is a large intracellular complex assembled by several different cell types in response to various damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). It consists of NLRP3 pattern recognition receptor (PRR), adaptor protein ASC and active form of caspase-1 and functions to coordinate a pro-inflammatory response by cleavage of IL-1 and IL-18 from their inactive forms. In our proposal, we will first demonstrate that the release of IL-1 from platelets following traumatic injury promotes platelet aggregation and venous thrombus formation. This will be achieved using a pharmacologic and genetic manipulation of IL-1 pathway and our murine model of polytrauma and DVT. Second, we will determine whether trauma-induced platelet-specific NLRP3 inflammasome assembly leads to IL-1 release from platelets. We will use genetic manipulation of NLRP3 specifically in platelets combined with our murine models of polytrauma and DVT. Together, these aims will provide robust evidence of platelet- specific NLRP3 inflammasome and IL-1 involvement in VTE formation following trauma. Identifying this novel pathway in trauma-induced VTE will allow us to devise more effective methods of VTE prophylaxis in trauma patients. Additionally, it will fundamentally advance our knowledge of platelet function as both an immune and a hemostatic agent.